Thoracic vertebrae fracture: Is it an indicator of abdominal injury?

PURPOSE: Traumatic vertebral fracture accounts for 10-15% of trauma related admissions. While the correlation between lumbar vertebral fractures and abdominal injuries is well established, the relationship between thoracic vertebral fractures (TVF) and abdominal injuries is comparatively less well elucidated. Using a large national trauma database, we aimed to examine the incidence and severity of associated abdominal injuries in blunt trauma patients suffering from TVF. METHODS: A retrospective cohort study using the Israeli National Trauma Registry was conducted. Patients with thoracic vertebrae spine fractures following blunt mechanisms of trauma between 1997 and 2018 were examined, comparing the incidence and severity of associated intraabdominal organs injuries with and without TVF. Demographics and outcomes between the two cohorts were compared. RESULTS: From 362,924 blunt trauma patients, 4967 (1.37%) had isolated TVF. Mean age was 49.8 years and 61.9% were males. The most common mechanism of injury was fall following by MVC. The patients with TVF had significantly higher rates of increased ISS score (ISS > 16, 28.45% vs. 10.42%, p < 0.001) and higher mortality rate (3.5% vs. 2%, p < 0.0001). Patients with TVF had 2-3 times more intraabdominal organ injuries (p < 0.001). The most commonly injured organ was spleen (3.28%); followed by liver (2.64%) and kidney (1.47%). An analysis of non-isolated thoracic spine fractures showed same distribution in age, ISS, mechanisms, patterns of intra-abdominal injury, mortality rate and laparotomy rate. CONCLUSION: Clinicians should have an elevated suspicion for intra-abdominal injuries when a thoracic spine fracture is identified, which may necessitate further evaluation.

Tolerability of non-ergot oral and transdermal dopamine agonists in younger and older Parkinson's disease patients: an European multicentre survey.

In older patients with Parkinson's disease (PD), the use of dopamine agonists (DA) has been limited due to uncertainties related to their tolerability in spite of potential gains with the advent of longer acting or transdermal therapies. Comparative real-life data addressing the tolerability of DA therapy across age ranges are currently sparse. This study addressed the tolerability (Shulman criteria, continued intake of DA therapy for at least 6 months) in PD patients across several European centres treated with long-acting and transdermal DA (Rotigotine skin patch, Ropinirole extended release, or Pramipexole prolonged release) as part of routine clinical care in younger and older PD patients. A medical record-based retrospective data capture and clinical interview-based follow-up survey of patients initiating or initiated on DA treatment (short and long acting) in a real-life setting. 425 cases were included [mean age 68.3 years (range 37-90), mean duration of disease 7.5 years (range 0-37), 31.5% older age (≥ 75 years of age)]. Tolerability was above 90% irrespective of age, with no significant differences between younger and older patients. Based on our findings, we suggest that long-acting/transdermal DA are tolerated in non-demented older patients, as well as in younger patients, however, with lower daily dose in older patients.

First comprehensive tool for screening pain in Parkinson's disease: the King's Parkinson's Disease Pain Questionnaire.

BACKGROUND AND PURPOSE: Pain is highly prevalent in Parkinson's disease (PD), impacting patients' ability, mood and quality of life. Detecting the presence of pain in its multiple modalities is necessary for adequate personalized management of PD. A 14-item, PD-specific, patient-based questionnaire (the King's Parkinson's Disease Pain Questionnaire, KPPQ) was designed corresponding to the rater-based KPP Scale (KPPS). The present multicentre study was aimed at testing the validity of this screening tool. METHODS: First, a comparison between the KPPQ scores of patients and matched controls was performed. Next, convergent validity, reproducibility (test-retest) and diagnostic performance of the questionnaire were analysed. RESULTS: Data from 300 patients and 150 controls are reported. PD patients declared significantly more pain symptoms than controls (3.96 ± 2.56 vs. 2.17 ± 1.39; P < 0.0001). The KPPQ convergent validity was high with KPPS total score (rS  = 0.80) but weak or moderate with other pain assessments. Test-retest reliability was satisfactory with kappa values ≥0.65 except for item 5, Dyskinetic pains (κ = 0.44), and the intraclass correlation coefficient (ICC) for the KPPQ total score was 0.98. After the scores of the KPPS were adapted for screening (0, no symptom; ≥1, symptom present), a good agreement was found between the KPPQ and the KPPS (ICC = 0.88). A strong correlation (rS  = 0.80) between the two instruments was found. The diagnostic parameters of the KPPQ were very satisfactory as a whole, with a global accuracy of 78.3%-98.3%. CONCLUSIONS: These results suggest that the KPPQ is a useful, reliable and valid screening instrument for pain in PD to advance patient-related outcomes.

Morphokinetics of human blastocyst expansion in vitro.

Time-lapse imaging offers new tools to study dynamic processes of development such as blastocyst formation and expansion. This study quantitatively describes expansion in human blastocysts from donated oocytes. Measurements of hourly interval rate of changes in the blastocoel cross-sectional area revealed oscillatory pulses having 2-4 h periodicities. Two types of oscillations were distinguished. An E-Type ('expansion') had positive peak and positive or slightly negative trough interval rate of change values, and these characterized most of the expansion period. A C-type ('contraction') represented an infrequent but notable contraction of the blastocoel with loss of blastocoel fluid. These were reversible within 2-4 h in both groups and followed by further expansion. Therefore, oscillatory pulses are an intrinsic property of the trophectoderm. The zona seems to variably dampen the amplitude of these pulses. Expansion kinetics were compared between blastocysts with known positive (KID+) or negative (KID-) implantation outcomes. Regression analysis suggests that expansion may be relatively restricted in KID- embryos blastulating at relatively later times. These data extend observations in other mammalian systems and may provide information useful for clinical selection algorithms.

A European multicentre survey of impulse control behaviours in Parkinson's disease patients treated with short- and long-acting dopamine agonists.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated primarily with dopamine agonist (DA) use. Comparative surveys of clinical occurrence of impulse control behaviours on longer acting/transdermal DA therapy across age ranges are lacking. The aim of this study was to assess the occurrence of ICDs in PD patients across several European centres treated with short- or long-acting [ropinirole (ROP); pramipexole (PPX)] and transdermal [rotigotine skin patch (RTG)] DAs, based on clinical survey as part of routine clinical care. METHODS: A survey based on medical records and clinical interviews of patients initiating or initiated on DA treatment (both short- and long-acting, and transdermal) across a broad range of disease stages and age groups was performed. RESULTS: Four hundred and twenty-five cases were included [mean age 68.3 years (range 37-90), mean duration of disease 7.5 years (range 0-37)]. ICD frequencies (as assessed by clinical interview) were significantly lower with RTG (4.9%; P < 0.05) compared with any other assessed DAs except for prolonged release PPX (PPX-PR). The rate of ICDs for PPX-PR (6.6%) was significantly lower than for immediate release PPX (PPX-IR) (19.0%; P < 0.05). Discontinuation rates of DA therapy due to ICDs were low. CONCLUSION: Our data suggest a relatively low rate of ICDs with long-acting or transdermal DAs, however these preliminary observational data need to be confirmed with prospective studies controlling for possible confounding factors.

King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation.

Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD.

Effect of teleradiology upon pattern of transfer of head injured patients from a rural general hospital to a neurosurgical referral centre: follow-up study.

INTRODUCTION: The optimal management strategy for patients with head injury admitted to a non-specialist hospital is uncertain. The aim of this study was to evaluate the outcomes of victims of head injury requiring hospitalisation but initially admitted to a rural level II trauma centre without a neurosurgical facility but with a system for neurosurgical consultation via teleradiology. METHODS: Patients admitted for head injury during 2006-2011 were included. Late transfer of patients initially hospitalised in the level II trauma centre was evaluated for treatment failure, defined as clinical or radiological deterioration. RESULTS: Five hundred and sixty-two patients were initially hospitalised in the level II trauma centre. Evaluation of late transfers showed that only 23 (4.1%) represented real treatment failures due to clinical or radiological deterioration. The clinical course was altered by primary intent to hospitalise patients in the level II trauma centre in only one patient. CONCLUSIONS: Selected patients with head trauma who have a pathological CT scan may be safely managed in level II trauma centres following neurosurgical consultation using teleradiology. Review of treatment failures is necessary to ensure proper ongoing management of a system in which neurosurgical patients are selectively transferred to trauma centres with neurosurgical capacity.

Do signs of abdominal wall injury on computed tomography predict intra-abdominal injury in trauma patients with a seatbelt sign?

BACKGROUND: A seatbelt sign in patients with blunt abdominal injury is associated with both abdominal wall and intra-abdominal injuries. This study aimed to assess the association between signs of abdominal wall injury on computed tomography (CT) and rates of intra-abdominal injury in patients with a blunt abdominal injury and a clinical seatbelt sign. METHODS: This study includes hemodynamically stable trauma patients with blunt abdominal injury and a clinical seatbelt sign who were hospitalized in two regional trauma centers in Israel, during 2014-2019. All data were collected via the medical center's trauma registry in both centers. RESULTS: We identified 123 stable blunt abdominal trauma patients with a seatbelt sign, of which 101 (82.1%) and 22 (17.9%) had a low-grade and high-grade abdominal wall injury according to CT findings, respectively. Laparotomy rates were significantly higher in patients with signs of high-grade abdominal wall injury (p<0.0001). No differences in the timing of laparotomy between low and high-grade injuries were found. CONCLUSIONS: In stable patients with blunt abdominal trauma and a clinical seatbelt sign, the severity of abdominal wall injury, as represented by CT findings, may predict a need for surgical treatment.

Time to surgery: Is it truly crucial in initially stable patients with penetrating injury?

BACKGROUND: Treatment recommendations for patients with penetrating abdominal injury are well established. Trauma victims with clear indications for surgery, should undergo immediate operative intervention without any delay or additional imaging. However, the optimal time for surgery remains unclear. There are some significant advantages in preoperative abdominal CT, including gathering essential information regarding a few difficult to reach anatomical areas, avoiding unnecessary explorations associated with increased morbidity and assessing the existence of extra-abdominal injuries that may have non-expectable impact on initial therapeutic plan. The aim of this study was to determine the impact of "time-to-surgery" on final medical outcomes in patients with penetrating abdominal trauma with normal blood pressure on admission. METHODS: A retrospective cohort study using the Israeli National Trauma Registry was conducted from 2000- 2018. This study included trauma patients with penetrating injuries and a systolic blood pressure of 90mmHg or above on admission. All patients included in the study were divided into three groups according to the time that lapsed from their admission to surgery: half an hour, an hour, and two hours. We assessed the outcome for each patient, including length of hospital stay, need for intensive care and mortality. Statistical analysis was performed using the Chi-square test, ANOVA test. A p-value of less than 0.05 was considered statistically significant. RESULTS: The study included 1,136 penetrating trauma patients. Among these, 78.0% (886) had sustained low-energy penetrating injury (SWPI) and 22.0% (250) had sustained high-energy penetrating injury (FAPI). Males accounted for 93.5% (1,062) of the patients. Mean age was 30.4. About 29% (327) of all the patients underwent surgery within 30 minutes from admission, 42% (475) within 30-60 min, and 29% (334) patients were operated within one to two hours. Patients who underwent surgery within 30 minutes, had worse ISS and GCS scores and were, therefore, more likely to have worse clinical outcomes. No other differences in outcomes were found in patients who were operated upon within 2 hours. CONCLUSIONS: Time to surgery within two hours from admission has no impact on final outcomes in trauma patients with penetrating injury and normal blood pressure on admission.

Three cases of delusional parasitosis caused by dopamine agonists.

We report three cases of delusional parasitosis (DP) in patients with well-established Parkinson's disease, all of whom were taking dopamine agonists. In all three cases, the DP resolved rapidly when the drug was withdrawn.

Consensus on resuscitative endovascular balloon occlusion of the Aorta: A first consensus paper using a Delphi method.

BACKGROUND: To further strengthen the evidence base on the use of Resuscitative Endovascular Balloon occlusion of the Aorta (REBOA) we performed a Delphi consensus. The aim of this paper is to establish consensus on the indications and contraindications for the use of REBOA in trauma and non-trauma patients based on the existing evidence and expertise. STUDY DESIGN: A literature review facilitated the design of a three-round Delphi questionnaire. Delphi panelists were identified by the investigators. Consensus was reached when at least 70% of the panelists responded to the survey and more than 70% of respondents reached agreement or disagreement. RESULTS: Panel members reached consensus on potential indications, contra-indications and settings for use of REBOA (excluding the pre hospital environment), physiological parameters for patient selection and indications for early femoral access. Panel members failed to reach consensus on the use of REBOA in patients in extremis (no pulse, no blood pressure) and the use of REBOA in patients with two major bleeding sites. CONCLUSIONS: Consensus was reached on indications, contra indications, physiological parameters for patient selection for REBOA and early femoral access. The panel did not reach consensus on the use of REBOA in patients in pre-hospital settings, patients in extremis (no pulse, no blood pressure) and in patients with 2 or more major bleeding sites. Further research should focus on the indications of REBOA in pre hospital settings, patients in near cardiac arrest and REBOA inflation times.

The use of aortic balloon occlusion in traumatic shock: first report from the ABO trauma registry.

PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique for temporary stabilization of patients with non-compressible torso hemorrhage. This technique has been increasingly used worldwide during the past decade. Despite the good outcomes of translational studies, clinical studies are divided. The aim of this multicenter-international study was to capture REBOA-specific data and outcomes. METHODS: REBOA practicing centers were invited to join this online register, which was established in September 2014. REBOA cases were reported, both retrospective and prospective. Demographics, injury patterns, hemodynamic variables, REBOA-specific data, complications and 30-days mortality were reported. RESULTS: Ninety-six cases from 6 different countries were reported between 2011 and 2016. Mean age was 52 ± 22 years and 88% of the cases were blunt trauma with a median injury severity score (ISS) of 41 (IQR 29-50). In the majority of the cases, Zone I REBOA was used. Median systolic blood pressure before balloon inflation was 60 mmHg (IQR 40-80), which increased to 100 mmHg (IQR 80-128) after inflation. Continuous occlusion was applied in 52% of the patients, and 48% received non-continuous occlusion. Occlusion time longer than 60 min was reported as 38 and 14% in the non-continuous and continuous groups, respectively. Complications, such as extremity compartment syndrome (n = 3), were only noted in the continuous occlusion group. The 30-day mortality for non-continuous REBOA was 48%, and 64% for continuous occlusion. CONCLUSIONS: This observational multicenter study presents results regarding continuous and non-continuous REBOA with favorable outcomes. However, further prospective studies are needed to be able to draw conclusions on morbidity and mortality.

The contribution of the Israeli trauma system to the survival of road traffic casualties.

BACKGROUND: According to the World Health Organization, over one million people die annually from traffic crashes, in which over half are pedestrians, bicycle riders and two-wheel motor vehicles. In Israel, during the last decade, mortality from traffic crashes has decreased from 636 in 1998 to 288 in 2011. Professionals attribute the decrease in mortality to enforcement, improved infrastructure and roads and behavioral changes among road users, while no credit is given to the trauma system. Trauma systems which care for severe and critical casualties improve the injury outcomes and reduce mortality among road casualties. GOALS: 1) To evaluate the contribution of the Israeli Health System, especially the trauma system, on the reduction in mortality among traffic casualties. 2) To evaluate the chance of survival among hospitalized traffic casualties, according to age, gender, injury severity and type of road user. METHODS: A retrospective study based on the National Trauma Registry, 1998-2011, including hospitalization data from eight hospitals. OUTCOMES: During the study period, the Trauma Registry included 262,947 hospitalized trauma patients, of which 25.3% were due to a road accident. During the study period, a 25% reduction in traffic related mortality was reported, from 3.6% in 1998 to 2.7% in 2011. Among severe and critical (ISS 16+) casualties the reduction in mortality rates was even more significant, 41%; from 18.6% in 1998 to 11.0% in 2011. Among severe and critical pedestrian injuries, a 44% decrease was reported (from 29.1% in 1998 to 16.2% in 2011) and a 65% reduction among bicycle injuries. During the study period, the risk of mortality decreased by over 50% from 1998 to 2011 (OR 0.44 95% 0.33-0.59. In addition, a simulation was conducted to determine the impact of the trauma system on mortality of hospitalized road casualties. Presuming that the mortality rate remained constant at 18.6% and without any improvement in the trauma system, in 2011 there would have been 182 in-hospital deaths compared to the actual 108 traffic related deaths. A 41% difference was noted between the actual number of deaths and the expected number. CONCLUSIONS: This study clearly shows that without any improvement in the health system, specifically the trauma system, the number of traffic deaths would be considerably greater. Although the health system has a significant contribution on reducing mortality, it does not receive the appropriate acknowledgment or resources for its proportion in the fight against traffic accidents.

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Androgen inhibition of follicle-stimulating hormone-stimulated luteinizing hormone receptor formation in cultured rat granulosa cells.

Since LH receptors are decreased in atretic follicles known to contain high androgen levels, we have studied the androgen modulation of LH receptor formation in vitro. Granulosa cells from hypophysectomized, diethylstilbestrol-treated rats were cultured for 3 days with FSH in the presence or absence of nonaromatizable androgens, dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol, or a synthetic androgen, R1881 (17 beta-hydroxy-17 alpha-methyl-4,9,11-estratrien-3-one). FSH increased LH receptor content in granulosa cells, while concomitant androgen treatment decreased LH receptor content in a dose- and time-dependent manner, without changing the equilibrium dissociation constant (Kd) for human CG. R1881 (10(-7) M), dihydrotestosterone (10(-6) M), and 5 alpha-androstane-3 alpha, 17 beta-diol (10(-6) M) inhibited LH receptor content by 68%, 65%, and 65%, respectively. Similar to earlier findings, these androgens enhanced FSH-stimulated progesterone biosynthesis and aromatase activity in the same cells. To study their LH responsiveness, androgen-treated cells were washed and reincubated for 2 more days with or without LH. Although basal progesterone production was elevated by R1881 pretreatment, the androgen-pretreated cells were less responsive to LH. Treatment with cyanoketone, an inhibitor of 3 beta-hydroxysteroid dehydrogenase, did not alter the inhibitory effects of R1881 on LH receptors, indicating that the androgen action is not mediated by endogenous progestins. Furthermore, R1881 inhibited the stimulation of LH receptor formation by forskolin, cholera toxin, and 8-bromo-cAMP, suggesting that androgens may inhibit LH receptor induction by affecting post-cAMP events. Estrogen treatment enhanced the FSH induction of LH receptor content, while concomitant addition of R1881 also suppressed the estrogen action. Thus, androgens inhibit FSH-induced functional LH receptors in cultured rat granulosa cells. The androgen effect is exerted, at least partially, at post-cAMP sites and is independent of changes in progestin biosynthesis.

Circulating luteinizing hormone pulse frequency in women with polycystic ovary syndrome.

To determine whether pulsatile LH frequency is altered in patients with the polycystic ovary syndrome (PCO) serum LH was measured every 10 min for 12 h (0800-2000 h) in nine patients. Six cycling women studied in the midfollicular (MF) or early follicular (EF) phases of their cycle served as controls. Three of these women were studied in both phases, yielding a total of nine control studies. In the PCO patients the mean LH pulse frequency was 12.1 +/- 0.7 (+/- SE) pulses/12 h. This value was indistinguishable from that of normal EF (12.1 +/- 0.4 pulses/12 h) or MF women (12.0 +/- 0.7 pulses/12 h). In contrast, the mean LH pulse amplitude in the PCO patients (12.2 +/- 2.7 mIU/mL) was higher (P less than 0.05) than that in normal women in either phase (EF, 6.2 +/- 0.8 mIU/mL; MF, 6.4 +/- 0.6 mIU/mL). These results suggest that the elevations in serum LH levels that occur in PCO patients are due primarily to increased LH pulse amplitude rather than increased pulse frequency.

Phorbol ester increases plasminogen activator inhibitor accumulation in cultures of human granulosa cells.

Proteolytic enzymes such as plasminogen activators (PAs) and collagenases are implicated in the process of ovarian follicle rupture. Data obtained in rats support the concept that PAs are both hormonally regulated and temporally related to the ovulatory process; however, such data are lacking in the human ovary. The recent identification of a family of PA inhibitors (PAIs) adds a new dimension to the control of PA activity, and in contrast to animal studies, the human preovulatory follicle is characterized by PA inhibitory activity. To initially examine the PA and PAI system in the human ovary, granulosa cells obtained from women undergoing gonadal hyperstimulation for in vitro fertilization were cultured in the presence or absence of the protein kinase-C activator, phorbol 12-myristate 13-acetate. Reverse fibrin autography of conditioned medium from control cells revealed the presence of a putative PAI with an apparent mol wt of 50,000. Phorbol ester stimulated the accumulation of this PAI in a specific and dose-dependent manner. Cumulus cells and noncumulus granulosa cells were similar in terms of presence and regulation of PAI. Immunoprecipitation with specific antisera revealed that this human granulosa cell PAI was immunochemically related to PAI-1. This identification was supported by quantitative analysis revealing a 3.7-fold increase in PAI-1 antigen, as assessed by a specific enzyme-linked immunoabsorbent assay. These findings are the first demonstration of the in vitro regulation of PAI activity in the human ovary.

Serum bioactive follicle-stimulating hormone during the human menstrual cycle and in hyper- and hypogonadotropic states: application of a sensitive granulosa cell aromatase bioassay.

A sensitive in vitro assay based on the stimulation of estrogen production by cultured rat granulosa cells was recently developed for the measurement of biologically active FSH. This bioassay system is specific for FSH, highly sensitive, and capable of measuring basal FSH levels in rat serum. The granulosa cell aromatase bioassay was improved by the use of additives known to enhance FSH activity and by pretreatment of serum with 12% polyethylene glycol to remove inhibitory substances. We applied this method to the measurement of bioactive FSH levels in serum samples from human subjects. As determined in daily blood samples during ovulatory menstrual cycles in seven women, bioactive FSH levels exhibited a pattern closely resembling that of immunoreactive FSH. The mean bioactive serum FSH levels were 29.9, 20.5, 39.2, and 14.8 mIU/ml for the early follicular phase, late follicular phase, preovulatory surge, and luteal phase, respectively. The bio- to immunoratio (B:I) throughout the menstrual cycle ranged from 1.4-3.4, with a mean of 2.5. The ratios for early follicular phase, late follicular phase, preovulatory surge, and luteal phase were 2.7, 2.3, 1.4, and 2.6, respectively. The correlation coefficient (r) of the serum FSH values obtained by bioassay and RIA was 0.91. FSH bioactivity was also measured in patients in each of the following categories with the following mean values: oral contraceptive pill users (undetectable), hypothalamic amenorrhea (18.7 mIU/ml; B:I, 2.6), premature ovarian failure (163 mIU/ml; B:I, 1.7), and postmenopausal women (191 mIU/ml; B:I, 1.6). These findings suggest that measurement of immunoreactive FSH levels correctly reflects the biological activity of FSH in serum of cycling women and patients in certain hyper- and hypogonadotropic states. The granulosa cell aromatase bioassay represents a new tool for future assessments of biologically active FSH in physiological and pathophysiological conditions.

Antioxidant potential of specific estrogens on lipid peroxidation.

Coronary heart disease (CHD) is the leading cause of death in postmenopause. Estrogen administration in postmenopause lowers the risk of CHD by 50%. A variety of estrogen preparations are currently used in postmenopausal hormone replacement therapy. It is unknown, however, if structural differences in the estrogen molecule influence the cardioprotective effects of estrogens. In this communication we have shown that equine estrogens (especially equilin) exhibit higher antioxidant potency (as measured by fatty acids and sterols oxidation) when compared to estrone and estradiol-17 beta.

The dependency of bioactive follicle-stimulating hormone secretion on gonadotropin-releasing hormone in hypogonadal and cycling women.

An antagonist analog of GnRH, (Ac-delta 3-Pro1,p-F-D-Phe2,D-Trp3,6)GnRH (4F-antagonist), was administered to normal women and women with hypergonadotropic hypogonadism. Serum FSH levels were determined by both the granulosa cell aromatase bioassay and RIA. The constant infusion of 4F-antagonist (30 micrograms/kg.h) to the four hypogonadal women resulted in a more pronounced decline in bioactive FSH (62%) than in immunoreactive FSH levels (30%), and the FSH bioactive to immunoreactive ratio decreased significantly (P less than 0.05). Infusion of 4F-antagonist in normal women in the midfollicular phase revealed a similar pattern of suppression of bioactive (64%) and immunoreactive FSH (29%). When 4F-antagonist was administered sc at a dose of 80 micrograms/kg twice daily for 3 days to normal women in the midfollicular phase of their cycles, the bioactive FSH response was biphasic, with the maximal decrease on the second day, followed by return to basal levels on the third day. Correspondingly, there was a precipitous decline in serum estradiol (apparent demise of the dominant follicle), followed by a progressive rise in estradiol levels. Thus, in contrast to immunoreactive FSH levels, bioactive FSH more clearly reflects the biological action of FSH on the follicle in response to GnRH antagonist administration in women. The disparity in the quantitative decline between serum bioactive and immunoreactive FSH levels after presumed blockade of the GnRH receptor may reflect the microheterogeneity of the FSH molecule and suggests that alterations in the biological activity of secreted FSH may be GnRH dependent.